Comprehensive genome analysis for hematopoietic cells of atomic bomb survivors

• Project/Area Number: 17H04209
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagasaki University
• Principal Investigator: MIYAZAKI Yasushi 長崎大学, 原爆後障害医療研究所, 教授 (40304943)
• Co-Investigator(Kenkyū-buntansha): 吉浦 孝一郎 長崎大学, 原爆後障害医療研究所, 教授 (00304931)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥15,470,000 (Direct Cost: ¥11,900,000、Indirect Cost: ¥3,570,000); Fiscal Year 2019: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 骨髄異形成症候群 / ゲノム / 原爆被爆者 / 放射線 / 染色体

Outline of Final Research Achievements

Ionizing radiation is a risk factor for myeloid neoplasms including myelodysplastic syndromes (MDS), and atomic bomb survivors have been shown to have a significantly higher risk of MDS. In this study, we performed genome analyses of MDS among survivors and found that proximally exposed patients had significantly fewer mutations in genes such as TET2 along the DNA methylation pathways, and they had a significantly higher rate of 11q deletions. Among the genes located in the deleted portion of chromosome 11, alterations of ATM was significantly more frequent in proximally exposed group with mutations identified on the remaining allele in two out of five cases. TP53, which is frequently mutated in therapy-related MDS, was equally affected between proximally and distally exposed patients. These results demonstrate that the genetic aberration profiles in MDS among atomic bomb survivors differed from those in therapy-related and de novo MDS.

Academic Significance and Societal Importance of the Research Achievements

今回の研究では、原爆放射線によって誘発されたと考えられる骨髄異形成症候群(MDS)において、これまで報告されている初発MDSあるいは治療関連MDSとは異なる特徴を持つ細胞遺伝学的変異、およびゲノム変異の存在が示された。これは、加齢に伴うMDS発症（初発例）、化学療法/放射線治療によるMDS発症とは異なった経緯によって被爆者MDSが発症してきた可能性を示している。今後、さらに詳細なゲノム変異研究や症例の蓄積によってこれまで知られていなかったMDSの発症機構を明らかにできる可能性があり、悪性腫瘍の病態を考える上で有用な情報を提供できると考えられる。

Research Products

• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center(米国)
• [Int'l Joint Research] スタンフォード大学(米国)
• [Int'l Joint Research] University Medical Centre Goettingen(ドイツ)
• [Int'l Joint Research] University Medical Centre Goettingen(ドイツ)
• [Journal Article] Persistent clonal cytogenetic abnormality with del(20q) from an initial diagnosis of acute promyelocytic leukemia. (2020)
  • Author(s): Fujioka M, Itonaga H, Kato T, Nannya Y, Hashimoto M, Kasai S, Toriyama E, Kamijo R, Taguchi M, Taniguchi H, Sato S, Atogami S, Imaizumi Y, Hata T, Moriuchi Y, Ogawa S, Miyazaki Y.
  • Journal Title: International Journal of Hematology Volume: 111 Issue: 2 Pages: 311-316
  • DOI: 10.1007/s12185-019-02731-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical impact of the loss of chromosome 7q on outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem cell transplantation (2019)
  • Author(s): Itonaga Hidehiro、Ishiyama Ken、Aoki Kazunari、Aoki Jun、Ishikawa Takayuki、Ohashi Kazuteru、Fukuda Takayuki、Ozawa Yukiyasu、Ota Shuichi、Uchida Naoyuki、Eto Tetsuya、Iwato Koji、Ohno Yuju、Takanashi Minoko、Ichinohe Tatsuo、Atsuta Yoshiko、Miyazaki Yasushi
  • Journal Title: Bone Marrow Transplantation Volume: - Issue: 9 Pages: 1471-1481
  • DOI: 10.1038/s41409-019-0469-5
  • NAID: 120006987799
  • Peer Reviewed
• [Journal Article] Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki (2019)
  • Author(s): Taguchi M, Mishima H, Shiozawa Y, Hayashida C, Kinoshita A, Nannya Y, Makishima H, Horai M, Matsuo M, Sato S, Itonaga H, Kato T, Taniguchi H, Imanishi D, Imaizumi Y, Hata T, Takenaka M, Moriuchi Y, Shiraishi Y, Miyano S, Ogawa S, Yoshiura K-i, Miyazaki Y
  • Journal Title: Haematologica Volume: 105 Issue: 2 Pages: 358-365
  • DOI: 10.3324/haematol.2019.219386
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study. (2019)
  • Author(s): Kawashima N, Akashi A, Nagata Y, Kihara R, Ishikawa Y, Asou N, Ohtake S, Miyawaki S, Sakura T, Ozawa Y, Usui N, Kanamori H, Ito Y, Imai K, Suehiro Y, Kitamura K, Sakaida E, Takeshita A, Suzushima H, Naoe T, Matsumura I, Miyazaki Y, Ogawa S, Kiyoi H
  • Journal Title: Ann Hematol Volume: 98 Issue: 1 Pages: 83-91
  • DOI: 10.1007/s00277-018-3492-5
  • NAID: 120006623799
  • Peer Reviewed / Open Access
• [Journal Article] Tamibarotene maintenance improved relapse-free survival of acute promyelocytic leukemia: a final result of prospective, randomized, JALSG-APL204 study. (2019)
  • Author(s): Takeshita A, Asou N, Atsuta Y, Sakura T, Ueda Y, Sawa M, Dobashi N, Taniguchi Y, Suzuki R, Nakagawa M, Tamaki S, Hagihara M, Fujimaki K, Furumaki H, Obata Y, Fujita H, Yanada M, Maeda Y, Usui N, Kobayashi Y, Kiyoi H, Ohtake S, Matsumura I, Naoe T, Miyazaki Y
  • Journal Title: Leukemia Volume: 33 Issue: 2 Pages: 358-370
  • DOI: 10.1038/s41375-018-0233-7
  • Peer Reviewed / Open Access
• [Journal Article] Chronic myeloid leukemia: Two mysteries (2019)
  • Author(s): Radivoyevitch Tomas、Jorgensen Trine N.、Lindner Daniel J.、Maciejewski Jaroslaw P.、Miyazaki Yasushi、Gale Robert Peter
  • Journal Title: Leukemia Research Volume: 79 Pages: 3-5
  • DOI: 10.1016/j.leukres.2019.02.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic Impact of Donor Source on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Adults with Chronic Myelomonocytic Leukemia: A Nationwide Retrospective Analysis in Japan (2018)
  • Author(s): Itonaga Hidehiro、Aoki Kazunari、Aoki Jun、Ishikawa Takayuki、Ishiyama Ken、Uchida Naoyuki、Sakura Toru、Ohashi Kazuteru、Kurokawa Mineo、Ozawa Yukiyasu、Matsuoka Ken-ichi、Nakamura Yukinori、Kimura Fumihiko、Iwato Koji、Nawa Yuichiro、Hirokawa Makoto、Kato Koji、Ichinohe Tatsuo、Atsuta Yoshiko、Miyazaki Yasushi
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 24 Issue: 4 Pages: 840-848
  • DOI: 10.1016/j.bbmt.2017.11.016
  • Peer Reviewed / Open Access
• [Journal Article] Clonal dynamics in a case of acute monoblastic leukemia that later developed myeloproliferative neoplasm. (2018)
  • Author(s): Sato S, Itonaga H, Taguchi M, Sawayama Y, Imanishi D, Tsushima H, Hata T, Moriuchi Y, Mishima H, Kinoshita A, Yoshiura KI, Miyazaki Y.
  • Journal Title: Int J Hematol. Volume: - Issue: 2 Pages: 213-217
  • DOI: 10.1007/s12185-018-2419-1
  • Peer Reviewed
• [Journal Article] Final analysis of the JALSG Ph+ALL202 study: tyrosine kinase inhibitor-combined chemotherapy for Ph+ALL (2018)
  • Author(s): Hatta Y, Mizuta S, Matsuo K, Ohtake S, Iwanaga M, Sugiura I, Doki N, Kanamori H, Ueda Y, Yoshida C, Dobashi N, Maeda T, Yujiri T, Monma F, Ito Y, Hayakawa F, Takeuchi J, Kiyoi H, Miyazaki Y, Naoe T
  • Journal Title: Ann Hematol Volume: 97 Issue: 9 Pages: 1535-1545
  • DOI: 10.1007/s00277-018-3323-8
  • Peer Reviewed / Open Access
• [Journal Article] Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes: Analysis from the International Working Group for Prognosis of MDS (2018)
  • Author(s): Miyazaki Y, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C
  • Journal Title: Leukemia Research Volume: 73 Pages: 51-57
  • DOI: 10.1016/j.leukres.2018.08.022
  • NAID: 120006987942
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia (2018)
  • Author(s): Matsuo Hidemasa、Itonaga Hidehiro、et al.
  • Journal Title: Blood Advances Volume: 2 Issue: 21 Pages: 2879-2889
  • DOI: 10.1182/bloodadvances.2018019398
  • NAID: 120006534600
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for the treatment of BCR-ABL1-negative atypical chronic myeloid leukemia and chronic neutrophil leukemia: A retrospective nationwide study in Japan (2018)
  • Author(s): Itonaga Hidehiro、Ota Shuichi、Ikeda Takashi、Taji Hirohumi、Amano Itsuto、Hasegawa Yuichi、Ichinohe Tatsuo、Fukuda Takahiro、Atsuta Yoshiko、Tanizawa Akihiko、Kondo Takeshi、Miyazaki Yasushi
  • Journal Title: Leukemia Research Volume: 75 Pages: 50-57
  • DOI: 10.1016/j.leukres.2018.11.003
  • NAID: 120006987880
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. (2018)
  • Author(s): Li JF, Dai YT, Kubota Y, Kiyoi H, Matsumura I, Miyazaki Y, Olsson L, Tan AM, Ariffin H, Chen J, Takita J, Yasuda T, Mano H, Johansson B, Yang JJ, Yeoh AE, Hayakawa F, Chen Z, Pui CH, Fioretos T, Chen SJ, Huang JY.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 50
  • DOI: 10.1073/pnas.1814397115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exome analysis of treatment-related AML after APL suggests secondary evolution (2018)
  • Author(s): Wang Tianjiao、Jacoby Meagan A.、Duncavage Eric J.、Miller Christopher A.、Heath Sharon、Rahme Ramy、Fenaux Pierre、Ades Lionel、Renneville Aline、Cassinat Bruno、Takeshita Akihiro、Asou Norio、Miyazaki Yasushi、Kiyoi Hitoshi、Ravandi Farhad、Westervelt Peter、Wartman Lukas D.、Welch John S.
  • Journal Title: British Journal of Haematology Volume: 印刷中 Issue: 5 Pages: 984-987
  • DOI: 10.1111/bjh.15681
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic analysis according to the 2017 ELN risk stratification by genetics in adult acute myeloid leukemia patients treated in the Japan Adult Leukemia Study Group (JALSG) AML201 study (2018)
  • Author(s): Harada Y、Nagata Y、Kihara R、Ishikawa Y、Asou N、Ohtake S、Miyawaki S、Sakura T、Ozawa Y、Usui N、Kanamori H、Ito Y、Imai K、Suehiro Y、Kobayashi S、Kitamura K、Sakaida E、Onizuka M、Takeshita A、Ishida F、Suzushima H、Ishizawa K、Naoe T、Matsumura I、Miyazaki Y、Ogawa S、Kiyoi H
  • Journal Title: Leukemia Research Volume: 66 Pages: 20-27
  • DOI: 10.1016/j.leukres.2018.01.008
  • NAID: 120006473597
  • Peer Reviewed
• [Journal Article] Distinct gene alterations with a high percentage of myeloperoxidase-positive leukemic blasts in de novo acute myeloid leukemia (2018)
  • Author(s): Kamijo Rena、Itonaga Hidehiro、Kihara Rika、Nagata Yasunobu、Hata Tomoko、Asou Norio、Ohtake Shigeki、Shiraishi Yuichi、Chiba Kenichi、Tanaka Hiroko、Miyano Satoru、Ogawa Seishi、Naoe Tomoki、Kiyoi Hitoshi、Miyazaki Yasushi
  • Journal Title: Leukemia Research Volume: 65 Pages: 34-41
  • DOI: 10.1016/j.leukres.2017.12.006
  • NAID: 120006988058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chromosomal analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki. (2018)
  • Author(s): Horai M, Satoh S, Matsuo M, Iwanaga M, Horio K, Jo T, Takasaki Y, Kawaguchi Y, Tsushima H, Yoshida S, Taguchi M, Itonaga H, Sawayama Y, Taguchi J, Imaizumi Y, Hata T, Moriuchi Y, Haase D, Yoshiura KI, Miyazaki Y.
  • Journal Title: Br J Haematol. Volume: 180 Issue: 3 Pages: 381-390
  • DOI: 10.1111/bjh.15050
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma (2017)
  • Author(s): Kataoka Keisuke、Iwanaga Masako、Yasunaga Jun-ichirou、et al.
  • Journal Title: Blood Volume: 131 Issue: 2 Pages: 215-225
  • DOI: 10.1182/blood-2017-01-761874
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG (2017)
  • Author(s): Sakura T、Hayakawa F、Sugiura I、Murayama T、Imai K、Usui N、Fujisawa S、Yamauchi T、Yujiri T、Kakihana K、Ito Y、Kanamori H、Ueda Y、Miyata Y、Kurokawa M、Asou N、Ohnishi K、Ohtake S、Kobayashi Y、Matsuo K、Kiyoi H、Miyazaki Y、Naoe T
  • Journal Title: Leukemia Volume: 32 Issue: 3 Pages: 626-632
  • DOI: 10.1038/leu.2017.283
  • Peer Reviewed / Open Access
• [Journal Article] JSH Guideline for Tumors of Hematopoietic and Lymphoid Tissues: Leukemia: 6. Myelodysplastic syndromes (MDS) (2017)
  • Author(s): Miyazaki Yasushi
  • Journal Title: International Journal of Hematology Volume: 106 Issue: 2 Pages: 151-159
  • DOI: 10.1007/s12185-017-2272-7
  • Peer Reviewed
• [Journal Article] Impact of genetic alterations in stem-cell transplantation for myelodysplasia and secondary acute myeloid leukemia. (2017)
  • Author(s): Yoshizato T, et. al., Sanada M, et. al., Ogawa S.
  • Journal Title: Blood Volume: 129 Issue: 17 Pages: 2347-2358
  • DOI: 10.1182/blood-2016-12-754796
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] TP53 State Dictates Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes (2019)
  • Author(s): Bernard E, Nannya Y, Shiozawa Y, Tuechler H, Malcovati L, Fenaux P, Miyazaki Y, Ebert BL, Bejar R, Cazzola M, Hellstrom Lindberg E, Ogawa S, Papaemmanuil E, et al.
  • Organizer: 第61回 アメリカ血液学会
  • Int'l Joint Research
• [Presentation] Genomic Analysis of Myelodysplastic Syndromes Among Nagasaki Atomic Bomb Survivors. (2018)
  • Author(s): Taguchi M, Mishima H, Shiozawa Y, Sato S, Horai M, Matsuo M, Itonaga H, Kato T, Taniguchi H, Imanishi D, Imaizumi Y, Hata T, Takenaka M, Makishima H, Nannya Y, Moriuchi Y, Ogawa S, Yoshiura KI, Miyazaki Y
  • Organizer: 第60回アメリカ血液学会
  • Int'l Joint Research
• [Presentation] Environmental Exposures and Myeloid Malignancies (2018)
  • Author(s): Yasushi Miyazaki
  • Organizer: 第60回アメリカ血液学会
  • Int'l Joint Research / Invited
• [Presentation] Chromosomal Analysis of Myelodysplastic Syndromes Among Atomic Bomb Survivors in Nagasaki. (2017)
  • Author(s): Miyazaki Y, Horai M, Iwanaga M, Sato S, Matsuo M, Horio K, Jo T, Takasaki Y, Kawaguchi Y, Tsushima H, Yoshida S, Taguchi M, Itonaga H, Sawayama Y, Taguchi J, Imaizumi Y, Hata T, Moriuchi Y, Haase D and Yoshiura K
  • Organizer: American Society of Hematology, 59th Annual Meeting and Exposition
  • Int'l Joint Research